Chromatin analysis of multiple myeloma cells following CBP/p300 inhibition and degradation (ChIP-Seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE160335 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) was discovered more than 2 decades ago and the enzymatic function of these enzymes are established as a major epigenetic regulatory mechanism of gene transcription. Thus, these epigenetic modifiers are involved in multiple diseases and represent attractive targets for therapeutic intervention. While HDAC inhibitors have been developed and approved by the FDA to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (here called p300/CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products and bisubstrate analogs such as Lys-CoA either lack potency and selectivity or suffer from poor cellular permeability. C646 is widely utilized as a tool to inhibit p300/CBP HAT activity, but its off-target activity and reactivity may limit its cellular specificity. Here, we describe A-485 as a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a pharmacologically active small molecule (A-485) bound to the catalytic active site of p300 HAT domain and demonstrate that A-485 is an acetyl-CoA competitive inhibitor of p300/CBP. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 robustly inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively drugging the catalytic activity of histone acetyltransferases, provide the framework for delineating the enzymatic functions of HATs, and pave the way for the development of novel therapeutics targeting HAT activity.
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Project description:This is a dataset generated by the Drosophila Regulatory Elements modENCODE Project led by Kevin P. White at the University of Chicago. It contains ChIP-chip data on Agilent 244K dual-color arrays for antibody: CBP/p300 at 12 different time-points of Drosophila development. Current Dataset: [GSM386269..GSM386277]: ChIP-chip of CBP in Drosophila embryos at 4-8 hours of development [GSM386279..GSM386287]: ChIP-chip of CBP in Drosophila embryos at 20-24 hours of development [GSM418309..GSM418317]: ChIP-chip of CBP in adult female Drosophila [GSM418318..GSM418326]: ChIP-chip of CBP in adult male Drosophila [GSM418335..GSM418343]: ChIP-chip of CBP in Drosophila embryos at 16-20 hours of development [GSM418454..GSM418462]: ChIP-chip of CBP in Drosophila L3 larvae [GSM418463..GSM418471]: ChIP-chip of CBP in Drosophila pupae [GSM442425..GSM442433]: ChIP-chip of CBP in Drosophila embryos at 0-4 hours of development [GSM443119..GSM443127]: ChIP-chip of CBP in Drosophila L1 larvae For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf For each combination of time-point and antibody, triplicate ChIP experiments have been performed and hybridized on Agilent 244K arrays. 3 arrays per genome have been used so that each time-point is a set of 9 tiling arrays.
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Project description:This is a dataset generated by the Drosophila Regulatory Elements modENCODE Project led by Kevin P. White at the University of Chicago. It contains ChIP-chip data on Agilent 244K dual-color arrays for antibody: CBP/p300 at 12 different time-points of Drosophila development. Current Dataset: [GSM386269..GSM386277]: ChIP-chip of CBP in Drosophila embryos at 4-8 hours of development [GSM386279..GSM386287]: ChIP-chip of CBP in Drosophila embryos at 20-24 hours of development [GSM418309..GSM418317]: ChIP-chip of CBP in adult female Drosophila [GSM418318..GSM418326]: ChIP-chip of CBP in adult male Drosophila [GSM418335..GSM418343]: ChIP-chip of CBP in Drosophila embryos at 16-20 hours of development [GSM418454..GSM418462]: ChIP-chip of CBP in Drosophila L3 larvae [GSM418463..GSM418471]: ChIP-chip of CBP in Drosophila pupae [GSM442425..GSM442433]: ChIP-chip of CBP in Drosophila embryos at 0-4 hours of development [GSM443119..GSM443127]: ChIP-chip of CBP in Drosophila L1 larvae For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf
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